心脏特异性敲除CD38对糖尿病心肌病的保护作用及其机制研究

糖脂代谢异常是导致糖尿病心肌病的重要原因，但其分子机制尚未阐明。CD38是哺乳类细胞NAD+的主要降解酶，我们前期发现敲除CD38减轻AngII诱导的心肌肥大及心脏缺血再灌注损伤，并减轻高脂饮食诱导的心脏氧化应激损伤。而CD38对糖尿病心肌病的影响尚未见报道。预实验发现糖尿病小鼠的心脏组织及高糖高脂刺激的心肌细胞CD38表达上调，而Sirt3表达下调，敲除CD38可改善糖尿病小鼠心功能并通过降低细胞凋亡及焦亡减轻心肌细胞损伤。因此，我们提出假说：敲除CD38可激活心肌细胞NAD+/Sirt3信号通路，继而减轻高糖高脂导致的心肌细胞凋亡/焦亡，抑制心肌纤维化从而对糖尿病心肌损伤发挥保护作用。本课题将利用全身及心脏特异性CD38敲除小鼠从整体、细胞、分子水平系统揭示心肌细胞CD38在糖尿病心肌病中的作用及机制，并试图阐明调控CD38转录的分子信号途径，为糖尿病心肌病的防治提供新思路和新靶点。

Abnormal glucose and lipid metabolism is an important cause of the diabetic cardiomyopathy in human being. However, the specific molecular mechanism is still unknown. In mammalian cells, CD38 is a major hydrolase for degradation of NAD+. Our previous studies showed that CD38 knockout mice were resistant to Ang-II induced cardiac hypertrophy and ischemia/reperfusion induced heart injury. In addition, CD38 deficiency could protect heart from high fat diet-induced oxidative stress. However, the roles and mechanisms of CD38 in diabetic cardiomyopathy is not explored. Our preliminary experimental results have shown that the expression of CD38 was up-regulated while the expression of Sirt3 was down-regulated in heart tissue from type 2 diabetic mice and cardiomyocytes stimulated by high glucose and palmitic acid. Moreover, CD38 deficiency improved heart function in diabetic mice and reduced myocardial cell damage by reducing apoptosis and pyroptosis. Therefore, we propose the hypothesis that CD38 deficiency may reduce cardiomyocyte apoptosis/pyroptosis caused by high glucose and high fat and reduce myocardial fibrosis via NAD+/Sirt3 signaling pathway, thereby playing protective roles in diabetic myocardial injury. In this study, the conventional and cardiac-specific CD38 knockout mice will be used to investigate the roles and mechanisms of CD38 in diabetic cardiomyopathy from the animal, cellular and molecular levels. In addition, we will elucidate the upstream signal molecules regulating CD38 transcription, thus providing new targets for the prevention and treatment of diabetic cardiomyopathy clinically.